Lesion studies in experimental animals document important roles for mesolimbic/mesocortial dopamine neurons lying in the ventral tegmental area in the reinforcing and rewarding properties of psychostimulants, and perhaps of other drugs of abuse. To test whether this "dopamine hypothesis" of psychostimulant reward is valid in humans, we examined psychostimulant effects on subjective ratings of mood in normal individuals and those with the dopamine cell lesions of Parkinson's disease. Prior anatomic studies suggest that ca. 60% of VTA neurons may be depleted in these brains, although the damage to the substantia nigra dopamine systems is greater. Subjective rating scales of mood, cardiovascular parameters, and locomotor functional ratings were performed after oral doses of placebo or methylphenidate using standard methods. Evidence for reduced responses in the Parkinson's disease subjects included significant reductions in methylphenidate-induced "good" feeling ratings on visual analog scales, and trends toward reductions in several associated measures in comparison to age- race- and sex-matched controls. These findings support dopaminergic theories of psychostimulant reward/reinforcement in humans. Future work will attempt to detect whether other individuals with dopamine system damage due to other pathologies share blunted methylphenidate responsiveness. Individuals with different levels of damage, as assessed by PET studies of dopamine transporter density, will also be evaluated.